Семьянов Алексей Васильевич

Личная информация

А.В. Семьянов закончил с отличием Нижегородский государственный университет по специальности биофизика в 1996 году. В течение последних 2 лет он совмещал учебу с работой в Институте теоретический и экспериментальной биофизики РАН (Пущино) под руководством проф. О.В. Годухина. А.В. Семьянов исследовал клеточные и молекулярные механизмы эпилептогенеза используя записи полевых потенциалов в срезах гиппокампа. Он обнаружил, что кратковременные повторяющиеся повышения внеклеточной концентрации калия приводят к долговременным изменениям возбудимости пирамидных нейронов поля СА1 гиппокампа, что делает структуру более чувствительной к развитию эпилептиформной активности (Neurosci. Let. 1997, 1997; Epilepsy Res. 2000). Эти данные вошли в кандидатскую диссертацию А.В. Семьянова, которая была защищена в 1998 году.

Вскоре после защиты кандидатской диссертации А.В. Семьянов получил позицию научного сотрудника в лаборатории проф. Дмитрия М. Кульмана в Институте Неврологии Университетского колледжа Лондона (Великобритания). Там он провел ряд исследований с использованием метода патч-кламп в срезах гиппокампа. В частности, он обнаружил, что глутамат вытекающий за пределы синаптической щели может достигать пресинаптических терминалей тормозных ГАМКергических синапсов, активировать на них метаботропные рецепторы глутамата и, таким образом, снижать вероятность высвобождения ГАМК (Neuron 2000). А.В. Семьянов обнаружил, что активация аксональных кайнатных рецепторов за счет спиловера глутамата может запускать эктопические потенциалы действия в аксонах гиппокампальных интернейронов (Nature Neurosci. 2001). Он описал клеточную специфичность тонической проводимости опосредованной активацией ГАМКА рецепторов посредством внесинаптической ГАМК (Nature Neurosci. 2003). Полученные данные о роли внесинаптической передачи сигналов в головном мозге легли в основу докторской диссертации А.В. Семьянова, защищенной в 2002 году в Пущино. В 2003 году проф. Дмитрий А. Русаков пригласил А.В. Семьянова в свою лабораторию в Институте Неврологии, где он освоил методы двухфотонного кальциевого имиджинга и фотоактивации глутамата.

В январе 2005, А.В. Семьянов переехал в Институт Мозга РИКЕН (Япония) по приглашению проф. Масао Ито, где основал свою независимую лабораторию. Лаборатория А.В. Семьянова использовала методы in vitro и in vivo электрофизиологии; двухфотонного кальциевого имиджинга и имиджинга потенциала с помощью второй гармоники. А.В. Семьянов исследовал механизмы и физиологическую значимость внесинаптической передачи и нейрон-глиального взаимодействия в гиппокампе. Он обнаружил, что тоническая активация внесинаптических ГАМКА рецепторов в гиппокампальных интернейронах имеет двойное действие сначала возбуждающее, затем тормозное в зависимости от изменения мембранной проводимости (Nature Commun 2011). Этот эффект является важным регулятором гиппокампальной ритмической активности (PNAS 2014). А.В. Семьянов обнаружил, что внесинаптические NMDA рецепторы в пирамидных нейронах гиппокампа находятся в связанном с внеклеточным глутаматом состоянии и активируются потенциалом действия, обратно распространяющимся в дендриты. Такая активация внесинаптических NMDA рецепторов запускает ранее неизвестный тип дендритной пластичности (Cell Reports 2012). А.В. Семьянов показал, что синаптические NMDA рецепторы вовлечены в ретроградную передачу сигнала в синапсе посредством высвобождения калия в синаптическую щель (Cell Reports 2013). Недавние исследования А.В. Семьянова посвящены ультраструктурным и ионным механизмам нейрон-глиального взаимодействия в гиппокампе.

В 2006 году, работая в Институте Мозга РИКЕН, А.В. Семьянов получил позицию профессора в Нижегородском государственном университете (ННГУ). Там он основал вторую лабораторию, комплементарную японской.

В апреле 2014, А.В. Семьянов вернулся в Россию и стал руководителем Нижегородского нейронаучного центра при ННГУ. В декабре 2014, в ННГУ был создан новый Институт Биологии и Биомедицины (ИББМ) путем слияния биологического факультета и биологических НИИ университета.  А.В. Семьянов стал директором ИББМ с задачей провести реформу с целью улучшения качества преподавания и научной результативности.  К преподаванию и научной работе были привлечены преподавали и ученые из зарубежных университетов. Некоторые из них открыли комплементарные лаборатории в ННГУ. В результате данной работы конкурс на биологические специальности за год вырос на 30%. Научные публикации ИББМ этого периода стали наиболее цитируемыми научными публикациями ННГУ.

В январе 2016 в ННГУ был создан новый НИИ нейронаук, в котором А.В. Семьянов стал директором и возглавляет по настоящее время. В октябре 2016 года А.В. Семьянов был избран в члены-корреспонденты Российской Академии Наук.  В сентябре 2017 года А.В. Семьянов стал руководителем отдела Молекулярной нейробиологии в Институте Биоорганической химии (Москва), где также возглавил лабораторию Внесинаптической передачи.

За последние годы усилиями А.В. Семьянова был организован ряд международных конференций, а также конференция Volga Neuroscience Meeting, которая получила широкую известность в мире (http://conf.neuro.unn.ru/). Им был организован совместно с проф. Алексеем Н. Верхратским (Великобритания) новый международный журнал Оpera Medica et Physiologica (http://www.operamedphys.org/).
 

Образование

Период обученияСтрана, городУчебное заведениеДополнительная информация
1991–1996 Нижний Новгород ННГУ биофизик
1996–1998 Пущино ПущГУ нейробиолог

Избранные публикации

  1. Jennings A., Tyurikova O., Bard L., Zheng K., Semyanov A., Henneberger C., Rusakov D.A. (2017). Dopamine elevates and lowers astroglial Ca2+ through distinct pathways depending on local synaptic circuitry. Glia 65 (3), 447–459 [+]

    Whilst astrocytes in culture invariably respond to dopamine with cytosolic Ca2+ rises, the dopamine sensitivity of astroglia in situ and its physiological roles remain unknown. To minimize effects of experimental manipulations on astroglial physiology, here we monitored Ca2+ in cells connected via gap junctions to astrocytes loaded whole-cell with cytosolic indicators in area CA1 of acute hippocampal slices. Aiming at high sensitivity of [Ca2+ ] measurements, we also employed life-time imaging of the Ca2+ indicator Oregon Green BAPTA-1. We found that dopamine triggered a dose-dependent, bidirectional Ca2+ response in stratum radiatum astroglia, a jagged elevation accompanied and followed by below-baseline decreases. The elevation depended on D1/D2 receptors and engaged intracellular Ca2+ storage and removal whereas the dopamine-induced [Ca2+ ] decrease involved D2 receptors only and was sensitive to Ca2+ channel blockade. In contrast, the stratum lacunosum moleculare astroglia generated higher-threshold dopamine-induced Ca2+ responses which did not depend on dopamine receptors and were uncoupled from the prominent inhibitory action of dopamine on local perforant path synapses. Our findings thus suggest that a single neurotransmitter-dopamine-could either elevate or decrease astrocyte [Ca2+ ] depending on the receptors involved, that such actions are specific to the regional neural circuitry and that they may be causally uncoupled from dopamine actions on local synapses. The results also indicate that [Ca2+ ] elevations commonly detected in astroglia can represent the variety of distinct mechanisms acting on the microscopic scale. GLIA 2017;65:447-459.

    ID:2044
  2. Pavlov I., Savtchenko L.P., Song I., Koo J., Pimashkin A., Rusakov D.A., Semyanov A. (2014). Tonic GABAA conductance bidirectionally controls interneuron firing pattern and synchronization in the CA3 hippocampal network. Proc. Natl. Acad. Sci. U.S.A. 111 (1), 504–9 [+]

    The spiking output of interneurons is key for rhythm generation in the brain. However, what controls interneuronal firing remains incompletely understood. Here we combine dynamic clamp experiments with neural network simulations to understand how tonic GABAA conductance regulates the firing pattern of CA3 interneurons. In baseline conditions, tonic GABAA depolarizes these cells, thus exerting an excitatory action while also reducing the excitatory postsynaptic potential (EPSP) amplitude through shunting. As a result, the emergence of weak tonic GABAA conductance transforms the interneuron firing pattern driven by individual EPSPs into a more regular spiking mode determined by the cell intrinsic properties. The increased regularity of spiking parallels stronger synchronization of the local network. With further increases in tonic GABAA conductance the shunting inhibition starts to dominate over excitatory actions and thus moderates interneuronal firing. The remaining spikes tend to follow the timing of suprathreshold EPSPs and thus become less regular again. The latter parallels a weakening in network synchronization. Thus, our observations suggest that tonic GABAA conductance can bidirectionally control brain rhythms through changes in the excitability of interneurons and in the temporal structure of their firing patterns.

    ID:2043
  3. Shih P.Y., Savtchenko L.P., Kamasawa N., Dembitskaya Y., McHugh T.J., Rusakov D.A., Shigemoto R., Semyanov A. (2013). Retrograde synaptic signaling mediated by K+ efflux through postsynaptic NMDA receptors. Cell Rep 5 (4), 941–51 [+]

    Synaptic NMDA receptors (NMDARs) carry inward Ca(2+) current responsible for postsynaptic signaling and plasticity in dendritic spines. Whether the concurrent K(+) efflux through the same receptors into the synaptic cleft has a physiological role is not known. Here, we report that NMDAR-dependent K(+) efflux can provide a retrograde signal in the synapse. In hippocampal CA3-CA1 synapses, the bulk of astrocytic K(+) current triggered by synaptic activity reflected K(+) efflux through local postsynaptic NMDARs. The local extracellular K(+) rise produced by activation of postsynaptic NMDARs boosted action potential-evoked presynaptic Ca(2+) transients and neurotransmitter release from Schaffer collaterals. Our findings indicate that postsynaptic NMDAR-mediated K(+) efflux contributes to use-dependent synaptic facilitation, thus revealing a fundamental form of retrograde synaptic signaling.

    ID:2042
  4. Wlodarczyk A.I., Sylantyev S., Herd M.B., Kersanté F., Lambert J.J., Rusakov D.A., Linthorst A.C., Semyanov A., Belelli D., Pavlov I., Walker M.C. (2013). GABA-independent GABAA receptor openings maintain tonic currents. J. Neurosci. 33 (9), 3905–14 [+]

    Activation of GABA(A) receptors (GABA(A)Rs) produces two forms of inhibition: phasic inhibition generated by the rapid, transient activation of synaptic GABA(A)Rs by presynaptic GABA release, and tonic inhibition generated by the persistent activation of perisynaptic or extrasynaptic GABA(A)Rs, which can detect extracellular GABA. Such tonic GABA(A)R-mediated currents are particularly evident in dentate granule cells in which they play a major role in regulating cell excitability. Here we show that in rat dentate granule cells in ex vivo hippocampal slices, tonic currents are predominantly generated by GABA-independent GABA(A) receptor openings. This tonic GABA(A)R conductance is resistant to the competitive GABA(A)R antagonist SR95531 (gabazine), which at high concentrations acts as a partial agonist, but can be blocked by an open channel blocker, picrotoxin. When slices are perfused with 200 nm GABA, a concentration that is comparable to CSF concentrations but is twice that measured by us in the hippocampus in vivo using zero-net-flux microdialysis, negligible GABA is detected by dentate granule cells. Spontaneously opening GABA(A)Rs, therefore, maintain dentate granule cell tonic currents in the face of low extracellular GABA concentrations.

    ID:2041
  5. Wu Y.W., Grebenyuk S., McHugh T.J., Rusakov D.A., Semyanov A. (2012). Backpropagating action potentials enable detection of extrasynaptic glutamate by NMDA receptors. Cell Rep 1 (5), 495–505 [+]

    Synaptic NMDA receptors (NMDARs) are crucial for neural coding and plasticity. However, little is known about the adaptive function of extrasynaptic NMDARs occurring mainly on dendritic shafts. Here, we find that in CA1 pyramidal neurons, back-propagating action potentials (bAPs) recruit shaft NMDARs exposed to ambient glutamate. In contrast, spine NMDARs are "protected," under baseline conditions, from such glutamate influences by peri-synaptic transporters: we detect bAP-evoked Ca(2+) entry through these receptors upon local synaptic or photolytic glutamate release. During theta-burst firing, NMDAR-dependent Ca(2+) entry either downregulates or upregulates an h-channel conductance (G(h)) of the cell depending on whether synaptic glutamate release is intact or blocked. Thus, the balance between activation of synaptic and extrasynaptic NMDARs can determine the sign of G(h) plasticity. G(h) plasticity in turn regulates dendritic input probed by local glutamate uncaging. These results uncover a metaplasticity mechanism potentially important for neural coding and memory formation.

    ID:2040
  6. Song I., Savtchenko L., Semyanov A. (2011). Tonic excitation or inhibition is set by GABA(A) conductance in hippocampal interneurons. Nat Commun 2, 376 [+]

    Inhibition is a physiological process that decreases the probability of a neuron generating an action potential. The two main mechanisms that have been proposed for inhibition are hyperpolarization and shunting. Shunting results from increased membrane conductance, and it reduces the neuron-firing probability. Here we show that ambient GABA, the main inhibitory neurotransmitter in the brain, can excite adult hippocampal interneurons. In these cells, the GABA(A) current reversal potential is depolarizing, making baseline tonic GABA(A) conductance excitatory. Increasing the tonic conductance enhances shunting-mediated inhibition, which eventually overpowers the excitation. Such a biphasic change in interneuron firing leads to corresponding changes in the GABA(A)-mediated synaptic signalling. The described phenomenon suggests that the excitatory or inhibitory actions of the current are set not only by the reversal potential, but also by the conductance.

    ID:2039
  7. Kochlamazashvili G., Senkov O., Grebenyuk S., Robinson C., Xiao M.F., Stummeyer K., GerardySchahn R., Engel A.K., Feig L., Semyanov A., Suppiramaniam V., Schachner M., Dityatev A. (2010). Neural cell adhesion molecule-associated polysialic acid regulates synaptic plasticity and learning by restraining the signaling through GluN2B-containing NMDA receptors. J. Neurosci. 30 (11), 4171–83 [+]

    The neural cell adhesion molecule (NCAM) is the predominant carrier of alpha2,8 polysialic acid (PSA) in the mammalian brain. Abnormalities in PSA and NCAM expression are associated with schizophrenia in humans and cause deficits in hippocampal synaptic plasticity and contextual fear conditioning in mice. Here, we show that PSA inhibits opening of recombinant NMDA receptors composed of GluN1/2B (NR1/NR2B) or GluN1/2A/2B (NR1/NR2A/NR2B) but not of GluN1/2A (NR1/NR2A) subunits. Deficits in NCAM/PSA increase GluN2B-mediated transmission and Ca(2+) transients in the CA1 region of the hippocampus. In line with elevation of GluN2B-mediated transmission, defects in long-term potentiation in the CA1 region and contextual fear memory in NCAM/PSA-deficient mice are abrogated by application of a GluN2B-selective antagonist. Furthermore, treatment with the glutamate scavenger glutamic-pyruvic transaminase, ablation of Ras-GRF1 (a mediator of GluN2B signaling to p38 MAPK), or direct inhibition of hyperactive p38 MAPK can restore impaired synaptic plasticity in brain slices lacking PSA/NCAM. Thus, PSA carried by NCAM regulates plasticity and learning by inhibition of the GluN2B-Ras-GRF1-p38 MAPK signaling pathway. These findings implicate carbohydrates carried by adhesion molecules in modulating NMDA receptor signaling in the brain and demonstrate reversibility of cognitive deficits associated with ablation of a schizophrenia-related adhesion molecule.

    ID:2038
  8. Pavlov I., Savtchenko L.P., Kullmann D.M., Semyanov A., Walker M.C. (2009). Outwardly rectifying tonically active GABAA receptors in pyramidal cells modulate neuronal offset, not gain. J. Neurosci. 29 (48), 15341–50 [+]

    Hippocampal pyramidal cell excitability is regulated both by fast synaptic inhibition and by tonically active high-affinity extrasynaptic GABA(A) receptors. The impact of tonic inhibition on neuronal gain and offset, and thus on information processing, is unclear. Offset is altered by shunting inhibition, and the gain of a neuronal response to an excitatory input can be modified by changing the level of "background" synaptic noise. Therefore, tonic activation of GABA(A) receptors would be expected to modulate offset and, in addition, to alter gain through a shunting effect on synaptic noise. Here we show that tonically active GABA(A) receptors in CA1 pyramidal cells show marked outward rectification, while the peaks of IPSCs exhibit a linear current-voltage relationship. As a result, tonic GABA(A) receptor-mediated currents have a minimal effect upon subthreshold membrane potential variation due to synaptic noise, but predominantly affect neurons at spiking threshold. Consistent with this, tonic GABA(A) receptor-mediated currents in pyramidal cells exclusively affect offset and not gain. Modulation of tonically active GABA(A) receptors by fluctuations in extracellular GABA concentrations or neuromodulators acting on high-affinity receptors potentially provides a powerful mechanism to alter neuronal offset independently of neuronal gain.

    ID:2037
  9. Wanaverbecq N., Semyanov A., Pavlov I., Walker M.C., Kullmann D.M. (2007). Cholinergic axons modulate GABAergic signaling among hippocampal interneurons via postsynaptic alpha 7 nicotinic receptors. J. Neurosci. 27 (21), 5683–93 [+]

    Homopentameric alpha7 nicotinic receptors have a high affinity for acetylcholine (ACh), are permeable to Ca2+ ions, and are abundant in hippocampal interneurons. Although nicotinic agonists evoke inward currents and Ca2+ transients in stratum radiatum interneurons, the role of endogenous ACh in modulating synaptic integration by interneurons is incompletely understood. Many cholinergic axonal varicosities do not have postsynaptic specializations, but alpha7 receptors frequently occur close to synaptic GABA(A) receptors. These observations raise the possibility that alpha7 nicotinic receptors activated by ACh released from cholinergic axons modulate GABAergic transmission in interneurons. We show that agonists of alpha7 receptors profoundly depress GABAergic IPSCs recorded in stratum radiatum interneurons in the CA1 region of the hippocampus. This depression is accompanied by a small increase in GABA release. Alpha7 nicotinic receptor agonists also depress GABA- or muscimol-evoked currents in interneurons, indicating that the major effect is a postsynaptic modulation of GABA(A) receptors. The depression of GABA-evoked currents is abolished by chelating Ca2+ in the recorded interneuron and attenuated by inhibitors of PKC. We also show that stimuli designed to release endogenous ACh from cholinergic axons evoke an alpha7 receptor-dependent heterosynaptic depression of GABAergic IPSCs in interneurons. This heterosynaptic modulation is amplified by blocking cholinesterases. These results reveal a novel mechanism by which cholinergic neurons modulate information processing in the hippocampus.

    ID:2036
  10. Scimemi A., Semyanov A., Sperk G., Kullmann D.M., Walker M.C. (2005). Multiple and plastic receptors mediate tonic GABAA receptor currents in the hippocampus. J. Neurosci. 25 (43), 10016–24 [+]

    Persistent activation of GABAA receptors by extracellular GABA (tonic inhibition) plays a critical role in signal processing and network excitability in the brain. In hippocampal principal cells, tonic inhibition has been reported to be mediated by alpha5-subunit-containing GABAA receptors (alpha5GABAARs). Pharmacological or genetic disruption of these receptors improves cognitive performance, suggesting that tonic inhibition has an adverse effect on information processing. Here, we show that alpha5GABAARs contribute to tonic currents in pyramidal cells only when ambient GABA concentrations increase (as may occur during increased brain activity). At low ambient GABA concentrations, activation of delta-subunit-containing GABAA receptors predominates. In epileptic tissue, alpha5GABAARs are downregulated and no longer contribute to tonic currents under conditions of raised extracellular GABA concentrations. Under these conditions, however, the tonic current is greater in pyramidal cells from epileptic tissue than in pyramidal cells from nonepileptic tissue, implying substitution of alpha5GABAARs by other GABAA receptor subtypes. These results reveal multiple components of tonic GABAA receptor-mediated conductance that are activated by low GABA concentrations. The relative contribution of these components changes after the induction of epilepsy, implying an adaptive plasticity of the tonic current in the presence of spontaneous seizures.

    ID:2035
  11. Semyanov A., Walker M.C., Kullmann D.M., Silver R.A. (2004). Tonically active GABA A receptors: modulating gain and maintaining the tone. Trends Neurosci. 27 (5), 262–9 [+]

    GABAA receptors not only respond to the local release of GABA from presynaptic terminals, but can also mediate a persistent 'tonic current'. This reflects the activation of high-affinity GABAA receptors by ambient GABA concentrations. Tonic GABAA-receptor-mediated signalling occurs in different brain regions, shows cell-type-specific differences in magnitude and pharmacology, and changes during brain development. Some clues to the adaptive significance of this phenomenon are beginning to emerge: in cerebellar granule cells, it alters the gain of transmission of rate-coded sensory information; in the hippocampus, it acts in a cell-type-specific manner to regulate the excitability of the network. Because tonic conductances can be modulated by changes in GABA release and uptake, and by modulators of high-affinity GABAA receptors including neurosteroids, this phenomenon provides a potentially important new window onto neuronal information processing and pathological states such as epilepsy.

    ID:2034
  12. Semyanov A., Walker M.C., Kullmann D.M. (2003). GABA uptake regulates cortical excitability via cell type-specific tonic inhibition. Nat. Neurosci. 6 (5), 484–90 [+]

    GABA(A) receptors can mediate both 'phasic' synaptic inhibition and a persistent 'tonic' form of signaling. We show that, in the presence of intact GABA uptake, guinea pig hippocampal interneurons, but not pyramidal cells, express a tonic GABA(A) receptor-mediated conductance. This conductance was pharmacologically distinct from spontaneous inhibitory postsynaptic currents (IPSCs). Inhibiting GABA uptake resulted in the expression of a comparable GABA(A) receptor-mediated tonic conductance in pyramidal cells. Reducing the tonic conductance in interneurons enhanced their excitability and the inhibitory drive to pyramidal cells. These results point to a role for cell type-dependent tonic inhibition in regulating cortical excitability.

    ID:2033
  13. Semyanov A., Kullmann D.M. (2001). Kainate receptor-dependent axonal depolarization and action potential initiation in interneurons. Nat. Neurosci. 4 (7), 718–23 [+]

    Kainate receptor agonists are powerful chemoconvulsants and excitotoxins. These properties are in part explained by depolarization of hippocampal principal neurons. However, kainate also depresses evoked inhibitory signals in pyramidal neurons, and promotes spontaneous GABA release from interneurons. The mechanisms underlying these phenomena are not fully understood, nor are the consequences for the inhibitory traffic among interneurons. We report that both the amplitude and the frequency of spontaneous IPSCs recorded in interneurons were enhanced by low concentrations of kainate, but action potential-independent IPSCs were unaffected. In the presence of GABA(A) receptor antagonists, kainate lowered the threshold for antidromic action potential generation, suggesting that interneuron axons are directly depolarized; this effect was mimicked by synaptically released glutamate. Kainate application also induced spontaneous antidromic action potentials. Axonal receptors are thus important in initiating the intense interneuronal activity triggered by kainate, which in turn influences inhibitory signaling to principal cells.

    ID:2032
  14. Semyanov A., Kullmann D.M. (2000). Modulation of GABAergic signaling among interneurons by metabotropic glutamate receptors. Neuron 25 (3), 663–72 [+]

    Synapses between hippocampal interneurons are an important potential target for modulatory influences that could affect overall network behavior. We report that the selective group III metabotropic receptor agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) depresses GABAergic transmission to interneurons more than to pyramidal neurons. The L-AP4-induced depression is accompanied by changes in trial-to-trial variability and paired-pulse depression that imply a presynaptic site of action. Brief trains of stimuli in Schaffer collaterals also depress GABAergic transmission to interneurons. This depression persists when GABA(B) receptors are blocked, is enhanced by blocking glutamate uptake, and is abolished by the group III metabotropic receptor antagonist (alpha-methylserine-O-phosphate (MSOP). The results imply that GABAergic transmission among interneurons is modulated by glutamate spillover from excitatory afferent terminals.

    ID:2031